发表机构
University of Rochester（罗切斯特大学）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究提出约束知识梯度（cKG）规则用于双药物剂量探索，通过高斯过程建模和单队列前瞻优化受试者分配与最终选择，在合成场景中相比现有方法在疗效上更优，但需权衡毒性风险。
AI 中文摘要
在双药物剂量探索试验中，下一队列应有助于确定最终选择的药物组合。我们研究了一种具有单队列前瞻性的约束知识梯度（cKG）规则，该规则更新疗效和连续毒性的独立高斯过程模型，重新应用平均毒性的概率准则，并评估由此产生的选择。我们在固定的剂量组合集上推导出确定性计算，在每次假设更新期间保持拟合的模型参数固定。我们将cKG与约束期望改进（cEI）以及两种仅基于毒性的规则——目标均方误差（tMSE）和熵——在四个合成场景中进行了比较。在主要基于阻塞性睡眠呼吸暂停（OSA）的场景中，按分层和五个概率截止值平均，cKG分配给高于真实平均毒性限值的组合的受试者少于tMSE（17.92%对27.08%），但在试验完成时更频繁地选择此类组合（18.80%对11.85%）。与cEI相比，cKG在最终选择时模拟的4%去饱和呼吸暂停低通气指数（AHI4）平均降低更高（7.46对6.72事件/小时），高于限值的最终选择更多（18.80%对10.50%），高于限值的分配也更多（17.92%对15.10%）。在各场景中，在更严格的毒性准则下，其相对于cEI的疗效优势较小。连续结局、未校准的毒性限值，以及当没有组合符合准则时仍选择某一组合的规则，限制了临床解释。分配和最终选择的毒性应与疗效分开报告。
英文摘要
In two-agent dose-finding trials, the next cohort should help identify a combination for final selection. We studied a constrained knowledge-gradient (cKG) rule with one-cohort lookahead that updates independent Gaussian-process models of efficacy and continuous toxicity, reapplies a probability criterion for mean toxicity, and evaluates the resulting selection. We derived a deterministic calculation over a fixed set of dose combinations, holding fitted model parameters fixed during each hypothetical update. We compared cKG with constrained expected improvement (cEI) and two toxicity-only rules, targeted mean squared error (tMSE) and entropy, in four synthetic scenarios. In the primary obstructive sleep apnea (OSA)-derived scenario, averaged equally over strata and five probability cutoffs, cKG assigned fewer participants to combinations above the true mean-toxicity limit than tMSE (17.92% versus 27.08%), but selected such combinations more often at trial completion (18.80% versus 11.85%). Compared with cEI, cKG had higher mean simulated reduction in the 4%-desaturation apnea-hypopnea index (AHI4) at final selection (7.46 versus 6.72 events/hour), more above-limit final selections (18.80% versus 10.50%), and more above-limit assignments (17.92% versus 15.10%). Across scenarios, its efficacy advantage over cEI was smaller under stricter toxicity criteria. Continuous outcomes, uncalibrated toxicity limits, and a rule that still selects a combination when none meets the criterion limit clinical interpretation. Allocation and final-selection toxicity should be reported separately, alongside efficacy.
Comments28 pages, 5 figures
